Methods of crystal precipitation

ABSTRACT

Crystals of paroxetine hydrochloride ½-hydrate are allowed to separate out by adding water to a solution or suspension comprising paroxetine hydrochloride and a polar organic solvent which contains no water or at most 60% by weight of water to adjust the water content to at least 70% by weight when crystals of paroxetine hydrochloride ½-hydrate are allowed to separate out in a water-containing polar organic solvent. Crystals of paroxetine hydrochloride ½-hydrate being not colored in pink can be allowed to separate out in the presence of hydrogen chloride when crystals of paroxetine hydrochloride ½-hydrate are allowed to separate out in water or a water-containing polar organic solvent.

This application is a 35 USC 371 application of PCT/JP2003/011805, filedSep. 17, 2003, which claims priority of Japanese application2002-273901, filed Sep. 19, 2002, pursuant to 35 USC 119.

TECHNICAL FIELD

Crystals of paroxetine hydrochloride ½-hydrate[(−)-(3S,4R)-4-(4-flourophenyl)-3-[3,4-methylenedioxy)phenoxymethyl]piperidinemonohydrochloride hemihydrate] have been used worldwide as anantidepressant. The present invention relates to a method for allowingsuch crystals of paroxetine hydrochloride ½-hydrate to separate outefficiently, and novel crystals of paroxetine hydrochloride ½-hydrate.

BACKGROUND ART

A conventional method for allowing crystals of paroxetine hydrochloride½-hydrate to separate out with a polar organic solvent such as a loweralcohol, which contains water or no water, is a method forcrystallization with 2-propanol containing 10% of water as a solvent(see, for instance, International Journal of Pharmaceutics, 42 (1988),135-143 (p. 136, left column, the first paragraph)). Also, there is amethod for crystallization by recrystallizing paroxetine hydrochlorideusing IMS (industrial methanol) as a solvent for recrystallization (see,for instance, Example 3(a) in EP 223403 B1 corresponding toJP-B-6-47587; and Example 4(a) of UK Patent Application No. 8526407).Also, there are some examples in which only water is used as a solventfor crystallization without using a polar organic solvent (see, forinstance, Examples 2 and 3(b) in EP 223403 B1; and Examples 3 and 4(b)in UK Patent Application No. 8526407).

In addition, an attempt to solve a problem of coloration in pink withparoxetine hydrochloride was made in WO 02/102382, which was laid opento public inspection after the priority date of the present application.In this method, when paroxetine hydrochloride is prepared by a reactionof a paroxetine base with HCl, HCl is used in an amount of less than 1mole equivalent or in such an amount that the pH becomes about 3 toabout 8, due to a disadvantage that, for instance, impurities areproduced when HCl (pH: at most 1) is used in a small excess amount. AsFar as the present inventors know, toluene which is a non-polar solventhas been used as a solvent for the preparation of paroxetinehydrochloride in the existence of a small excess amount of HCl (see EP223403 B1 and UK Patent Application No. 8526407).

DISCLOSURE OF INVENTION

The inventors have intensively studied various methods for allowingcrystals of paroxetine hydrochloride ½-hydrate to separate out with apolar organic solvent to provide a method for crystallization, notcausing the above problems. As a result, the present inventors havefound that crystals of paroxetine hydrochloride ½-hydrate separate outin a high yield when water is added to a solution or suspension ofparoxetine hydrochloride, the solvent of which is a polar organicsolvent containing no water or at most 60% by weight of water, to adjustthe water content to at least 70% by weight, and have completed thepresent invention. The present inventors found that the solubility ofparoxetine hydrochloride ½-hydrate becomes particularly higher in apolar organic solvent containing 10 to 60% by weight of water than thatin a polar organic solvent containing no water, with the exception ofexamples such as methanol, and that crystals efficiently separate outwhen water is added to the solution or suspension, to adjust the watercontent to at least 70% by weight, and the present invention has beenthus completed.

In addition, the present inventors found that a problem such ascoloration of crystals of paroxetine hydrochloride ½-hydrate obtained bya method for crystallization in an aqueous solvent or a polar organicsolvent containing water in pink can be solved by allowing crystals toseparate out in the presence of hydrogen chloride, and completed thepresent invention.

Specifically, one of the present inventions is:

-   (1) a method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out, characterized in that water is added to a    solution or suspension comprising paroxetine hydrochloride and a    polar organic solvent which contains no water or at most 60% by    weight of water, to adjust the water content to at least 70% by    weight, when crystals of paroxetine hydrochloride ½-hydrate are    allowed to separate out in a water-containing polar organic solvent;-   (2) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to the item (1) mentioned above,    wherein the solution or suspension of a solid or oily paroxetine    hydrochloride is prepared, and water is added to the solution or    suspension to adjust the water content to at least 70% by weight;-   (3) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to the item (1) mentioned above,    wherein the solution or suspension of crystals of paroxetine    hydrochloride is prepared, and water is added to the solution or    suspension to adjust the water content to at least 70% by weight;-   (4) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to the item (1) mentioned above,    wherein the solution or suspension of crystals of paroxetine    hydrochloride anhydrate is prepared, and water is added to the    solution or suspension to adjust the water content to at least 70%    by weight;-   (5) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to the item (1) mentioned above,    wherein the solution or suspension of crystals of 2-propanol solvate    of paroxetine hydrochloride anhydrate obtained by crystallization in    2-propanol is prepared, and water is added to the solution or    suspension to adjust the water content to at least 70% by weight;-   (6) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to the item (1) mentioned above,    wherein the solution or suspension of crystals of paroxetine    hydrochloride ½-hydrate is prepared, and water is added to the    solution or suspension to adjust the water content to at least 70%    by weight;-   (7) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to any one of the items (1)    to (6) mentioned above, wherein water is added to the solution or    suspension comprising paroxetine hydrochloride and a polar organic    solvent containing 15 to 55% by weight of water;-   (8) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to any one of the items (1)    to (6) mentioned above, wherein water is added to the solution or    suspension comprising paroxetine hydrochloride and a polar organic    solvent containing 20 to 50% by weight of water;-   (9) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to any one of the items (1)    to (8) mentioned above, wherein water is added to the solution or    suspension comprising paroxetine hydrochloride at 40° to 60° C.;-   (10) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to any one of the items (1)    to (9) mentioned above, wherein water is added to the solution or    suspension of paroxetine hydrochloride, and then the resulting    solution or suspension is cooled to 0° to 10° C.;-   (11) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to any one of the items (1)    to (10) mentioned above, wherein the polar organic solvent is a    lower alcohol or a ketone;-   (12) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to any one of the items (1)    to (11) mentioned above, wherein the lower alcohol is 2-propanol;    and-   (13) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to any one of the items (1)    to (12) mentioned above, wherein hydrogen chloride is present in the    solution or suspension of paroxetine hydrochloride.

Also, another of the present invention is:

-   (14) a method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out, characterized in that hydrogen chloride    is present when crystals of paroxetine hydrochloride ½-hydrate are    allowed to separate out from the solution or suspension of    paroxetine hydrochloride in which water or a water-containing polar    organic solvent is used as a solvent, with the exception of the case    where concentrated hydrochloric acid is added to an aqueous solution    of paroxetine acetate;-   (15) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to the item (14) mentioned    above, wherein the pH of the solution or suspension of paroxetine    hydrochloride is at most 2;-   (16) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to the item (14) or (15)    mentioned above, wherein the solution or suspension of a solid or    oily paroxetine hydrochloride is prepared, and water is added to the    solution or suspension to adjust the water content to at least 70%    by weight;-   (17) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to the item (14) or (15)    mentioned above, wherein the solution or suspension of crystals of    paroxetine hydrochloride is prepared, and water is added to the    solution or suspension to adjust the water content to at least 70%    by weight;-   (18) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to the item (14) or (15)    mentioned above, wherein the solution or suspension of crystals of    paroxetine hydrochloride anhydrate is prepared, and water is added    to the solution or suspension to adjust the water content to at    least 70% by weight;-   (19) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to the item (18) mentioned    above, wherein the crystals of paroxetine hydrochloride anhydrate    are crystals of 2-propanol solvate of paroxetine hydrochloride    anhydrate obtained by crystallization in 2-propanol;-   (20) the method for allowing crystals of paroxetine hydrochloride    ½-hydrate to separate out according to the item (14) or (15)    mentioned above, wherein the solution or suspension of crystals of    paroxetine hydrochloride ½-hydrate is prepared, and water is added    to the solution or suspension to adjust the water content to at    least 70% by weight;-   (21) crystals of paroxetine hydrochloride ½-hydrate, moisturized    with water or a polar organic solvent containing water,    characterized in that the crystals are not colored in pink;-   (22) crystals of paroxetine hydrochloride ½-hydrate, characterized    in that the pH of the supernatant of the suspension prepared by    suspending 1 g of the crystals in 10 g of distilled water is 3 to 6;    and-   (23) a process for preparing crystals of paroxetine hydrochloride    ½-hydrate being not colored in pink, comprising dissolving crystals    of paroxetine hydrochloride ½-hydrate being colored in pink in a    solvent for allowing crystals to separate out, characterized in that    the crystals are purified in the presence of hydrogen chloride in an    amount at least equimolar with the paroxetine hydrochloride    ½-hydrate.

BEST MODE FOR CARRYING OUT THE INVENTION

One of the methods for crystallization of the present invention is amethod as described in any one of the items (1) to (13) above (Invention1). The embodiment of this method is described below.

According to this method, a solution or suspension of paroxetinehydrochloride and a polar organic solvent which contains no water or atmost 60% by weight of water is first prepared.

The paroxetine hydrochloride may be in a solid state such as acrystalline state or an amorphous state, or an oily state which meansthat the paroxetine hydrochloride has not yet been solidified. Also, thesolution or suspension of paroxetine hydrochloride can be used. Theparoxetine hydrochloride is particularly preferably in a crystallinestate, because crystals of paroxetine hydrochloride ½-hydrate having ahigher purity can be obtained from this crystalline paroxetinehydrochloride when the method of the present invention is carried out.

The crystals can be any of crystals of paroxetine hydrochloride½-hydrate and crystals of paroxetine hydrochloride anhydrate. In thecase of crystals of paroxetine hydrochloride ½-hydrate, the method forcrystallization of the present invention is carried out mainly for thepurpose of purification of crystals. The paroxetine hydrochlorideanhydrate can be any of Form 2 described in International Journal ofPharmaceutics, 42 (1988), 135-143, and various non-solvate or solvatecrystals as described in WO 96/24595, JP-B-6-47587, EP 223403 B1, EP0812827 A1 and like. Practically preferable are crystals of 2-propanolsolvate of paroxetine hydrochloride anhydrate containing 2-propanol,which are crystallized from 2-propanol (the content of 2-propanol isexemplified by 14% by weight or 3% by weight or so). These crystals maybe wet crystals obtained by separating the crystals from a suspension ofcrystals by means of filtration or the like, that is, crystals fromwhich a solvent for crystallization has not yet been sufficientlyremoved by drying. There can be cited, for instance, crystals of2-propanol solvate of paroxetine hydrochloride anhydrate containing2-propanol, prepared by crystallizing from 2-propanol, which ismoisturized with 2-propanol as a solvent for crystallization, asdisclosed in item 1) of Example 9.

The solution or suspension of paroxetine hydrochloride is exemplified bythe followings, but is not limited to the exemplified ones. One exampleis a solution or suspension of paroxetine hydrochloride, obtained bysubjecting a precursor of paroxetine hydrochloride, for example,N-tert-butyloxycarbonyl-paroxetine to treating with hydrogen chloride,to deprotect the N-tert-butyloxycarbonyl group. This is a case where themethod for crystallization of the present invention is carried out byusing the reaction solution as it is without the isolation of paroxetinehydrochloride when the reaction solution is one containing paroxetinehydrochloride obtained by the above reaction at the post-treatmentstage, and its solvent is one of the polar organic solvents as describedabove such as 2-propanol. Another example is a case where paroxetinehydrochloride is obtained by the salt-exchange of an acid salt ofparoxetine, the acid of which is other than hydrochloric acid, such asacetate, with hydrogen chloride. When the solvent for the salt-exchangereaction used in this case is, for instance, one of the polar organicsolvents used in the present invention as described in Example 2, themethod for crystallization of the present invention can be carried outby using the solution or suspension of paroxetine hydrochloride obtainedby the above salt-exchange reaction as it is without the isolation ofparoxetine hydrochloride in some cases.

In the case where the solution or suspension of paroxetine hydrochlorideis obtained by converting the precursor, acid salt or the like intoparoxetine hydrochloride as described above, when the solvent is not oneof the polar organic solvents used in the present invention, the solventis exchanged for a solvent used in the present invention without theisolation of paroxetine hydrochloride, and then the solution orsuspension is used for the method of the present invention.

The polar organic solvent as referred to herein is an organic solventwhich is miscible with water and has a relative dielectric constant ofpreferably 5 to 50, more preferably 15 to 40 at 25° C. [see, “Newedition, Solvent Pocket Book,” pp. 1-2, edited by Synthetic OrganicChemistry Association, published by Ohmsha, Jun. 10, 1994].Representative examples of the polar organic solvent include loweralcohols having 1 to 5 carbon atoms, such as methanol, ethanol and2-propanol, ketones including symmetric or asymmetric, lowerdialkylketones having 2 to 5 carbon atoms, such as acetone and methylethyl ketone, tetrahydrofuran, and the like. From the viewpoint of thesolubility of paroxetine hydrochloride, the safety in terms of aresidual solvent contained in pharmaceuticals, and the like, 2-propanol,ethanol and acetone are especially preferred. From the viewpoint ofpractical value, 2-propanol is especially preferred. The polar organicsolvent may be a mixed solvent of two or more kinds of the polar organicsolvents mentioned above.

The polar organic solvent may contain water. In this case, the watercontent is at most 60% by weight from the viewpoint of the solubility ofparoxetine hydrochloride. Although the preferred range of the contentvaries with the kind of the solvent, the water content is preferably 10to 60% by weight, more preferably 15 to 55% by weight, still morepreferably about 20 to 50% by weight, with the exception of methanol.When the water content is within this range, the solubility ofparoxetine hydrochloride is high. It is preferable to increase thesolubility of paroxetine hydrochloride by controlling the water contentin order to allow crystals of paroxetine hydrochloride ½-hydrate havinga high purity to separate out even in the case of the suspension.

The solution or suspension of paroxetine hydrochloride is prepared byusing as a solvent a polar organic solvent which does not contain wateror contains water, as described above. The process for preparing thesolution or suspension may be any process, as long as the processeventually provides the above solution or suspension. In the case wherethe solution or suspension is prepared by using isolated paroxetinehydrochloride, the paroxetine hydrochloride is usually mixed with asolvent.

In another case, the solution or suspension of paroxetine hydrochlorideis obtained by converting the precursor, acid salt or the like intoparoxetine hydrochloride, as described above. In this case, water may beadded to adjust the water content as occasion demands.

In the present invention, either of the solution or the suspension maybe used, as long as it contains paroxetine hydrochloride, and thesolution is preferable from the viewpoint of the preparation of purifiedcrystals.

When the solution or suspension of paroxetine hydrochloride is prepared,it is preferable that the solution or suspension is usually warmed orheated so that paroxetine hydrochloride is dissolved as much aspossible, in order to increase the solubility of paroxetinehydrochloride, because the possibility of obtaining crystals having ahigher purity is increased. However, when the temperature is excessivelyincreased, the crystals are likely to be decomposed, so that thetemperature is usually adjusted to a temperature of 40° to 60° C. Tomerely obtain crystals of paroxetine hydrochloride ½-hydrate withoutintending to increase the purity, the temperature may be a temperatureequal to or higher than the temperature mentioned above or a temperatureequal to or lower than the temperature mentioned above, or may be roomtemperature.

The amount of the polar organic solvent which contains water or no wateris not limited to specified ones, as long as the solution or suspensioncan be prepared. The amount of the polar organic solvent is usually 1 to10 parts by weight, preferably 2 to 5 parts by weight, based on 1 partby weight of paroxetine hydrochloride, from the viewpoint of giving asolution or suspension which is easily handled. When the solution isprepared, the solution may be purified by treating with activatedcarbon.

In the present invention, water is added to the solution or suspensionof paroxetine hydrochloride prepared as mentioned above, to adjust thewater content in the polar organic solvent containing water to at least70% by weight, preferably 75 to 95% by weight, more preferably 80 to 90%by weight, to allow crystals to separate out.

The method for adding water is not limited to specified ones, as long aswater added is diffused sufficiently throughout the solution orsuspension of paroxetine hydrochloride and a large amount of crystals donot separate out at a time. When a large amount of crystals separate outat a time, the crystals tend to be too fine, so that the crystals aredifficult to be separated or got out, and the crystals tend to becontaminated with impurities. Usually, water is added dropwise to thesolution or suspension with stirring.

The addition rate, temperature and the like are controlled to preventthe crystallization in a large amount during the addition of water. Thetemperature of water added is preferably a temperature equal to orslightly lower than the temperature at which the solution or suspensionis prepared, and usually 40° to 60° C. When water is added to a solutioncomprising paroxetine hydrochloride and 2-propanol containing at most60% by weight of water or no water to adjust the water content to 80 to90% by weight, substantially little crystallization is usually observedeven at the stage where the water has been completely added.

After the addition of water, the resulting solution or suspension iscooled, to allow crystals to separate out. As a specific method forcrystallization, conventional means being widely used for usualcrystallization are employed. Specifically, the cooling rate iscontrolled so that a large amount of crystals do not separate out.Preferably, once crystals begin to separate out, this temperature ismaintained for a certain period of time, to allow crystal growth andsuppress the crystallization of too small crystals. The time period isseveral tens of minutes to one hour, which differs depending on thescale of production, and may be longer in a large-scale production insome cases. Crystals can be allowed to separate out by adding a seedcrystal to promote the crystallization.

Thereafter, in order to allow crystals to separate out sufficiently, thesolution or suspension is further cooled, and its temperature isadjusted to a temperature of 0° to 10° C., preferably 0° to 5° C. Inaccordance with conventional means, the solution or suspension isusually maintained at this temperature for a certain period of time, tocomplete the crystallization. The time period is several tens of minutesto one hour, which differs depending on the scale of production, and maybe longer in a large-scale production in some cases.

Cooling after the addition of water and maintaining the temperature asdescribed above are usually carried out under stirring, from theviewpoint of achieving uniform temperature throughout the solution andthe viewpoint of crystallization without maldistribution in a container.

Thereafter, the crystals of paroxetine hydrochloride ½-hydrate beingallowed to separate out by the method of the present invention areseparated by a conventional method such as filtration, washed and dried.It is preferable that hydrogen chloride is present in the solution orsuspension of paroxetine hydrochloride in the above-mentioned methods of(1) to (13) for crystallization of the present invention as describedbelow, from the viewpoint of the prevention of the resulting crystalsfrom coloration in pink.

Another method for crystallization of the present invention (Invention2) is a method described in any one of the items (15) to (21) forallowing crystals of paroxetine hydrochloride ½-hydrate to separate out,characterized in that hydrogen chloride is present when crystals ofparoxetine hydrochloride ½-hydrate are allowed to separate out from thesolution or suspension of paroxetine hydrochloride in which water or awater-containing polar organic solvent is used as a solvent, with theexception of the case where concentrated hydrochloric acid is added to asolution of paroxetine acetate.

According to this method, a problem arisen in the method for allowingcrystals of paroxetine hydrochloride ½-hydrate to separate out from thesolution or suspension of paroxetine hydrochloride in which water or awater-containing polar organic solvent is used as a solvent, such ascoloration of the crystals in pink can be solved. For instance,according to the above-mentioned methods of (1) to (13) forcrystallization, crystals being not colored in pink are obtained whenhydrogen chloride is present in the solution or suspension of paroxetinehydrochloride.

The term “hydrogen chloride is present,” as referred to herein, meansthat hydrogen chloride other than the hydrogen chloride constitutingparoxetine hydrochloride is present.

Also, in Invention 2, when hydrogen chloride other than the hydrogenchloride constituting the paroxetine hydrochloride is present in anamount at least equimolar with the paroxetine hydrochloride, decolorizedand purified crystals are obtained from the crystals being colored inpink. The crystals being colored in pink are obtained, for instance, bytreating the crystals of paroxetine hydrochloride ½-hydrate with waterat such a high temperature as 100° C.

The solution or suspension of paroxetine hydrochloride used in Invention2, the solvent of which is water or water-containing polar organicsolvent may be any solution or suspension, and include, for instance,one prepared by using 2-propanol containing 10% by weight of water as asolvent for crystallization as described in International Journal ofPharmaceutics, 42 (1988), 135-143, in particular, on p. 136, leftcolumn, the first paragraph; and those prepared by using IMS (industrialmethyl alcohol) or water as a solvent for recrystallization as describedin JP-B-6-47587, Example 2 of EP 223403 and the like. Also, the solutionand suspension may include the solutions or suspensions comprisingparoxetine hydrochloride usable in Invention 1. Incidentally,JP-B-6-47587 and Example 2 of EP 223403 disclose that crystals ofparoxetine hydrochloride ½-hydrate are allowed to separate out by addingconcentrated hydrochloric acid to an aqueous solution of paroxetineacetate, but there is no description concerning the prevention of thecrystals from coloration in pink in the these publications. Moreover,these documents do not at all disclose that solid or oily paroxetinehydrochloride being isolated is dissolved in water or a water-containingpolar organic solvent, and that hydrogen chloride is presented in thesolution. Incidentally, concentrated hydrochloric acid refers to aconcentrated hydrochloric acid having a meaning being usually employed,and is an aqueous solution prepared by dissolving hydrogen chloride(HCl) gas in water to an approximately saturated solution. Morespecifically, the concentrated hydrochloric acid as used herein means anaqueous solution of hydrogen chloride having a hydrogen chlorideconcentration of at least 35%, as specified in JIS (Japanese IndustrialStandard).

The paroxetine hydrochloride and the organic polar solvent include thosedescribed for Invention 1. The water content in the water-containingpolar organic solvent may be any content, as long as crystals ofparoxetine hydrochloride ½-hydrate are allowed to separate out. Thewater content is at least 5% by weight, in consideration of the amountwhich would cause a problem of coloration in pink. The paroxetinehydrochloride includes those described for Invention 1.

As the preparation of the solution or suspension of paroxetinehydrochloride, there can be cited those explained in Invention 1, exceptthat the water content is not limited to at most 60% by weight.

In Invention 2, sources for hydrogen chloride other than the hydrogenchloride constituting the paroxetine hydrochloride are exemplified byhydrochloric acid which is an aqueous solution of hydrogen chloride; asolution prepared by dissolving hydrogen chloride in the polar organicsolvent according to the present invention; and hydrogen chloride gasitself.

The method for supplying hydrogen chloride may be any method, as long asthe method allows hydrogen chloride to be present in the step ofcrystallization in Invention 2, and does not interfere with thecrystallization in Invention 2. A solution of hydrogen chloride orhydrogen chloride gas is usually supplied to the solution or suspensionof paroxetine hydrochloride, or water or a water-containing polarorganic solvent prior to the preparation of the solution or suspension.

The amount of the hydrogen chloride other than the hydrogen chlorideconstituting the paroxetine hydrochloride may be at least 0.05 times,preferably at least 0.1 times the amount (mole) of paroxetinehydrochloride. When crystals of paroxetine hydrochloride ½-hydrate beingcolored in pink are purified to give colorless crystals, the hydrogenchloride is required in an amount at least equimolar with the paroxetinehydrochloride. The amount of the hydrogen chloride can be up to 2 timesthe amount (mole) of paroxetine hydrochloride from the viewpoint ofsuppressing the coloration in pink. The hydrochloric acid can be addedin an amount greater than the amount mentioned above. However, if theamount is so much, for instance, the amount is ten times the amount ofparoxetine hydrochloride, and then dissolution of the paroxetinehydrochloride would be insufficient. Even so, such a large amount ofhydrochloric acid can be employed with no problem for obtaining crystalsof paroxetine hydrochloride ½-hydrate with suppressed coloration inpink.

When hydrogen chloride is used in the amount mentioned above, the pH ofthe solution or suspension comprising paroxetine hydrochloride will beat most 2. Also, when hydrogen chloride is used in an amount of at least0.1 times the amount (mole) of paroxetine hydrochloride, the pH will beat most 1.5. According to the Examples mentioned later, the pH isdetermined for the filtrate obtained after filtering crystals, and thispH is considered to demonstrate the pH of the solution or suspensionwhen the crystals are allowed to separate out.

The method for crystallization of paroxetine hydrochloride ½-hydratefrom the solution or suspension of paroxetine hydrochloride in whichhydrogen chloride exists can be any method, as long as paroxetinehydrochloride ½-hydrate is allowed to separate out. In case of a warmedsolution or suspension, a conventional method for cooling as it is, or amethod for adding water to cool as in Invention 1 can be cited. Whenwarming is not employed, a method for adding water can be used. Aftercrystals are allowed to separate out, usually, the solution orsuspension is further cooled to at most 10° C., practically 0° to 5° C.,to complete the crystallization. Thereafter, the crystals being allowedto separate out are subjected to filtration, washing and the like, andthen isolated. The crystals moisturized with the solvent forcrystallization just after this isolation are colored not in pink but inwhite according to Invention 2. According to a method forcrystallization in which hydrogen chloride is absent, crystals beingmoisturized with the solvent tend to be colored in pink.

Then the crystals are further dried to obtain white crystals ofparoxetine hydrochloride ½-hydrate being not colored in pink.

The crystals of paroxetine hydrochloride ½-hydrate obtained in Invention2 were suspended in the amount of 1 g in 10 g of distilled water, andthe pH of the supernatant of the suspension was measured. As a result,the pH was 3 to 6, usually 3 to 5.5, commonly 4.5 to 5.5, which is lowerthan the supernatant of the suspension of crystals obtained in theabsence of hydrogen chloride.

Next, the present invention is further explained on the basis of thefollowing examples, but the scope of the present invention is notlimited only to these examples.

EXAMPLE 1

To a mixed solution of 30.0 g of 2-propanol and 30.0 g of water wasadded 10.0 g (27.34 mmol) of a 2-propanol solvate of a paroxetinehydrochloride anhydrate (containing about 3% by weight of 2-propanol)under nitrogen gas stream to dissolve the solvate at room temperature.Another 50 mL of water was added thereto. In the course of cooling themixture to 5° C., crystals separated out at 20° C. After being stirredat 4° to 5° C. under ice cooling for 1 hour, the mixture was filtered atthe same temperature. The residue was washed with a solution composed of2.0 g of 2-propanol and 8.0 g of water, to give crystals colored inpink. The crystals were dried under reduced pressure at 60° C., to give8.35 g of crystals of a paroxetine hydrochloride ½ hydrate (yield: 81.5%by weight). Its water content was 2.51% by weight (theoretical watercontent: 2.40% by weight). The X-ray powder diffraction pattern (XRD)agreed with that of a reference material. The pH of the filtrate was5.75.

EXAMPLE 2

To a mixed solution of 30.0 g of 2-propanol and 28.0 g of water wasadded 10.64 g (27.34 mmol) of paroxetine acetate under nitrogen gasstream to dissolve the acetate at room temperature. Next, 3.13 g(equivalent to 30.05 mmol of hydrogen chloride) of 35% by weighthydrochloric acid and 50 mL of water were sequentially added to thesolution. In the course of cooling the mixture to 5° C., crystalsseparated out at 20° C. After being stirred at 4 °to 5° C. under icecooling for 1 hour, the mixture was filtered at the same temperature.The residue was washed with a solution of 2.0 g of 2-propanol and 8.0 gof water to give wet crystals (white). The crystals were dried underreduced pressure at a bath temperature of at most 40° C., to give 9.40 gof crystals (white) of a paroxetine hydrochloride ½ hydrate (yield:91.8% by weight). The XRD agreed with that of a reference material. ThepH of the filtrate was 1.39. The water content was 2.48% by weight(theoretical water content: 2.40% by weight).

EXAMPLE 3

To a mixed solution of 15.00 g of 2-propanol and 0.14 g of 35%hydrochloric acid (equivalent to 1.37 mmol of hydrogen chloride) wasadded 5.00 g (13.67 mmol) of a 2-propanol solvate of paroxetinehydrochloride anhydrate (containing about 3% by weight of 2-propanol)under nitrogen gas stream, and the mixture was heated to 50° C. Next, 25mL of water was added thereto at the same temperature. In the course ofcooling the mixture to 5° C., crystals separated out at 14° C. Afterbeing stirred at 14° to 24° C. for 1 hour and kept at 2° to 5° C. underice cooling for 1 hour, the mixture was filtered at the sametemperature. The residue was washed with 5 mL of water, to give wetcrystals (white). The crystals were dried under reduced pressure at 60°C., to give 4.25 g of crystals (white) of a paroxetine hydrochloride ½hydrate (yield: 88.3% by weight). The XRD agreed with that of areference material. The water content was 2.50% by weight (theoreticalwater content: 2.40% by weight). Its pH of the filtrate was 1.49.

EXAMPLE 4

To a mixed solution of 15.00 g of 2-propanol, 5.74 g of water and 14.24g (136.70 mmol) of 35% hydrochloric acid was added 5.00 g (13.67 mmol)of a 2-propanol solvate of paroxetine hydrochloride anhydrate(containing about 3% by weight of 2-propanol) under nitrogen gas stream.Although the mixture was heated to 58° C., the solvate was notdissolved. Next, 25 mL of water was added thereto at the sametemperature, and the mixture was cooled to 5° C. After being kept at 3°to 5° C. under ice cooling for 1 hour, the mixture was filtered at thesame temperature, and the residue was washed with 5 mL of water, to givewet crystals (white). The crystals were dried under reduced pressure at60° C., to give 4.62 g of crystals (white) of a paroxetine hydrochloride½ hydrate (yield: 90.2% by weight). The XRD agreed with that of areference material. Its water content was 2.48% by weight (theoreticalwater content: 2.40% by weight). The pH of the filtrate was measured. Asa result, the pH was 0.0.

EXAMPLE 5

To a mixed solution of 15.00 g of 2-propanol, 14.07 g of water and 1.42g of 35% hydrochloric acid (equivalent to 13.67 mmol of hydrogenchloride) was added 5.00 g (13.67 mmol) of a 2-propanol solvate of aparoxetine hydrochloride anhydrate (containing about 3% by weight of2-propanol) under nitrogen gas stream, and the mixture was heated to 40°C. to dissolve the solvate. Next, 25 mL of water was added thereto atthe same temperature, and the mixture was cooled to 5° C. After beingkept at 2° to 5° C. under ice cooling for 1 hour, the mixture wasfiltered at the same temperature, and the residue was washed with 5 mLof water, to give wet crystals (white). The crystals were dried underreduced pressure at 60° C., to give 4.67 g of crystals (white) of aparoxetine hydrochloride ½ hydrate (yield: 91.2% by weight). The XRDagreed with that of a reference material. The water content was 2.50% byweight (theoretical water content: 2.40% by weight).

EXAMPLE 6

To a mixed solution of 10.00 g of 2-propanol, 9.07 g of water and 1.42 g(equivalent to 13.67 mmol of hydrogen chloride) of 35% hydrochloric acidwas added 5.00 g (13.67 mmol) of a 2-propanol solvate of a paroxetinehydrochloride anhydrate (containing about 3% by weight of 2-propanol)under nitrogen stream, and the mixture was heated to 50° C. Next, 30 mLof water was added thereto at the same temperature. In the course ofcooling the mixture to 5° C., crystals separated out at 38° C. Afterbeing stirred at 38° to 40° C. for 30 minutes and kept at 3° to 5° C.under ice cooling for 1 hour, the mixture was filtered at the sametemperature. The residue was washed with 5 mL of water, to give wetcrystals (white). The crystals were dried under reduced pressure at 60°C., to give 4.80 g of crystals (white) of a paroxetine hydrochloride ½hydrate (yield: 93.8% by weight). The XRD agreed with that of areference material. The water content was 2.50% by weight (theoreticalwater content: 2.40% by weight).

EXAMPLE 7

To a mixed solution of 10.00 g of 2-propanol, 9.91 g of water and 0.14 gof 35% hydrochloric acid (equivalent to 1.367 mmol of hydrogen chloride)was added 5.00 g (13.67 mmol) of a 2-propanol solvate of a paroxetinehydrochloride anhydrate (containing about 3% by weight of 2-propanol)under nitrogen gas stream, and the mixture was heated to 50° C. Next, 30mL of water was added thereto at the same temperature. In the course ofcooling the mixture to 5° C., crystals separated out at 33° C. Afterbeing stirred at 32° to 33° C. for 30 minutes and kept at 2° to 5° C.under ice cooling for 30 minutes, the mixture was filtered at the sametemperature, and the residue was washed with 5 mL of water, to give wetcrystals (white). The crystals were dried under reduced pressure at 60°C., to give 4.82 g of crystals (white) of a paroxetine hydrochloride ½hydrate (yield: 94.1% by weight). The XRD agreed with that of areference material. The water content was 2.57% by weight (theoreticalwater content: 2.40% by weight).

EXAMPLE 8

To 38.11 g of a toluene solution containing 7.04 g (16.39 mmol) of crude(−)-(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[3,4-methylene-dioxyphenyl)oxymethyl]piperidinewas added 4.27 g of 35% hydrochloric acid (equivalent to 41.01 mmol ofhydrogen chloride) under nitrogen gas stream, and deprotection reactionof tert-butoxycarbonyl group was carried out at 68° to 70° C. for 2hours. The completion of the reaction was confirmed with HPLC. Next, 40mL of water was added thereto, to form phase separation (three layers)at 70° C. The upper layer (toluene layer) was removed from the mixture,and the intermediate layer (aqueous layer) and the lower layer (oillayer) were collected. To the intermediate layer and the lower layer,10.0 g of 2-propanol was added to form a single layer. In addition, 0.33g of activated carbon was added thereto and the mixture was stirred at62° to 67° C. for 15 minutes, and thereafter the activated carbon wasfiltered off. In the course of cooling the resulting solution to 5° C.,crystals separated out at 28° C. After being stirred at 38° to 40° C.for 30 minutes and kept at 2° to 5° C. under ice cooling for 30 minutes,the suspension was filtrated at the same temperature. The residue waswashed with a solution composed of 1.0 g of 2-propanol and 4.0 g ofwater, to give wet crystals. The crystals were dried under reducedpressure at 60° C., to give 5.10 g of crystals of a paroxetinehydrochloride ½-hydrate (yield: 85.0% by weight). The XRD agreed withthat of a reference material. The water content was 2.70% by weight(theoretical water content: 2.40% by weight).

EXAMPLE 9

Under nitrogen gas stream, 311.91 g of a 2-propanol solution containing42.95 g (100 mmol) of crude(−)-(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[3,4-methylenedioxyphenyl)oxymethyl]piperidinewas heated to 65° C., and 26.55 g of a 2-propanol solution of 20.6%hydrogen chloride (equivalent to 150 mmol of hydrogen chloride) wasadded dropwise thereto. The deprotection reaction of tert-butoxycarbonylgroup was carried out at 68° to 73° C. for 2 hours. The completion ofthe reaction was confirmed with HPLC. Next, 93 mL of 2-propanolcontaining isobutene was distilled off under normal pressure. Duringthis procedure, 93.5 mL of 2-propanol was added dropwise thereto tomaintain the amount of the liquid. Further, 2.41 g of activated carbonwas added thereto, the mixture was stirred at 80° to 82° C. for 15minutes, and thereafter the activated carbon was filtered off. Thefilter cake was washed with 43 mL of 2-propanol. After refluxing thefiltrate for 15 minutes, in the course of cooling the solution to 5° C.,crystals separated out at 55° C. After being kept at 5° C. under icecooling for 1 hour, the suspension was filtrated at the sametemperature. The residue was washed with 94.5 mL of 2-propanol, to give59.80 g (calculated yield after drying: 86.5% by weight) of wet crystalsof a 2-propanol solvate of a paroxetine hydrochloride anhydrate(saturated with 2-propanol; containing about 14% by weight of2-propanol). The crystals were divided into some portions to carry outthe following experiments 1) to 3).

1) To a mixed solution of 8.04 g of 2-propanol, 15.18 g of water and0.22 g (equivalent to 2.09 mmol of hydrogen chloride) of 35%hydrochloric acid was added 14.94 g (corresponding to 20.96 mmol of dryproduct) of the wet crystals of a 2-propanol solvate of a paroxetinehydrochloride anhydrate under nitrogen stream, and the mixture washeated to 50° C. Next, 45.96 g of water was added thereto at the sametemperature. In the course of cooling the mixture to 5° C., crystalsseparated out at 31° C. After being stirred at 31° to 34° C. for 30minutes and kept at 2° to 5° C. under ice cooling for 30 minutes, themixture was filtered at the same temperature. The residue was washedwith 7.7 mL of water, to give wet crystals (white). The crystals weredried under reduced pressure at 60° C., to give 7.42 g of crystals(white) of a paroxetine hydrochloride ½ hydrate (yield: 94.5% byweight). The XRD agreed with that of a reference material. The watercontent was 2.57% by weight (theoretical water content: 2.40% byweight). The pH of the supernatant of a suspension prepared bysuspending 1 g of the crystals in 10 g of distilled water was 5.21.

2) Wet crystals of a 2-propanol solvate of a paroxetine hydrochlorideanhydrate in an amount of 16.10 g were dried under reduced pressure at25° C., to give 9.55 g of a 2-propanol solvate of a paroxetinehydrochloride anhydrate containing 14.4% by weight of 2-propanol.

Next, 7.16 g (16.76 mmol) of this 2-propanol solvate of a paroxetinehydrochloride anhydrate was added to a mixed solution of 11.23 g of2-propanol, 12.15 g of water and 0.17 g of 35% hydrochloric acid(equivalent to 1.68 mmol of hydrogen chloride) under nitrogen gasstream, and the mixture was heated to 50° C. Subsequently, 49.05 g ofwater was added thereto at the same temperature. In the course ofcooling the mixture to 5° C., crystals separated out at 33° C. Afterbeing stirred at 33° to 38° C. for 30 minutes and kept at 2° to 5° C.for 30 minutes, the mixture was filtered at the same temperature. Theresidue was washed with 8.2 mL of water, to give wet crystals (white).The crystals were dried under reduced pressure at 60° C., to give 6.00 gof crystals (white) of a paroxetine hydrochloride ½ hydrate (yield:95.5% by weight). The XRD agreed with that of a reference material. Thewater content was 2.60% by weight (theoretical water content: 2.40% byweight). The pH of the supernatant of a suspension prepared bysuspending 1 g of the crystals in 10 g of distilled water was 5.51.

3) The above-mentioned wet crystals of a 2-propanol solvate of aparoxetine hydrochloride anhydrate in an amount of 13.05 g were driedunder reduced pressure at 80° C., to give 6.90 g of a 2-propanol solvateof a paroxetine hydrochloride anhydrate containing 3.0% by weight of2-propanol.

Next, 5.00 g (13.26 mmol) of this 2-propanol solvate of a paroxetinehydrochloride anhydrate was added to a mixed solution of 9.55 g of2-propanol, 9.61 g of water and 0.14 g (equivalent to 1.33 mmol ofhydrogen chloride) of 35% hydrochloric acid under nitrogen gas stream,and the mixture was heated to 50° C. Subsequently, 29.10 g of water wasadded thereto at the same temperature. In the course of cooling themixture to 5° C., crystals separated out at 30° C. After being stirredat 30° to 35° C. for 30 minutes and kept at 10 to 5° C. under icecooling for 30 minutes, the mixture was filtered at the sametemperature. The residue was washed with 4.9 mL of water, to give wetcrystals. The crystals were dried under reduced pressure at 60° C., togive 4.71 g of crystals (white) of a paroxetine hydrochloride ½ hydrate(yield: 94.8% by weight). The XRD agreed with that of a referencematerial. The water content was 2.60% by weight (theoretical watercontent: 2.40% by weight). The pH of the supernatant of a suspensionprepared by suspending 1 g of the crystals in 10 g of distilled waterwas 4.98.

EXAMPLE 10

Under nitrogen gas stream, 5.00 g (13.34 mmol) of crystals of aparoxetine hydrochloride ½ hydrate which had been once colored in pinkwere added to a mixed solution of 10.00 g of 2-propanol, 9.07 g of waterand 1.39 g (equivalent to 13.34 mmol of hydrogen chloride) of 35%hydrochloric acid, and the mixture was heated to 50° C. Next, 30 mL ofwater was added thereto at the same temperature. In the course ofcooling the mixture to 5° C., crystals separated out at 36° C. Afterbeing stirred at 36° to 39° C. for 30 minutes and kept at 1° to 5° C.under ice cooling for 1 hour, the mixture was filtered at the sametemperature. The residue was washed with 5 mL of water, to give wetcrystals (white). The crystals were dried under reduced pressure at 60°C., to give 4.91 g of crystals (white) of a paroxetine hydrochloride ½hydrate (yield: 98.2% by weight). The XRD agreed with that of areference material. The water content was 2.55% by weight (theoreticalwater content: 2.40% by weight).

EXAMPLE 11

Under nitrogen gas stream, 7.50 g (20.01 mmol) of crystals of aparoxetine hydrochloride ½ hydrate being colored in pink were added to amixed solution of 15.0 g of 2-propanol, 9.09 g of water and 2.08 g(equivalent to 20.01 mmol of hydrogen chloride) of 35% hydrochloricacid, and the mixture was heated to 50° C. Next, 45 mL of water wasadded thereto at the same temperature. In the course of cooling themixture to 5° C., crystals separated out at 37° C. After being stirredat 37° to 40° C. for 30 minutes and kept at 2° to 5° C. under icecooling for 30 minutes, the mixture was filtered at the sametemperature. The residue was washed with 7.5 g of water, to give wetcrystals. The crystals were dried under reduced pressure at 60° C., togive 7.33 g of crystals (yellowish white) of a paroxetine hydrochloride½ hydrate (yield: 97.7% by weight).

In the above-mentioned example, when 35% hydrochloric acid was notadded, the crystals of a paroxetine hydrochloride ½ hydrate were coloredin pink.

EXAMPLE 12

To a mixed solution of 5.0 g of 2-propanol, 4.91 g of water and 0.14 g(equivalent to 1.367 mmol of hydrogen chloride) of 35% hydrochloric acidwas added 5.00 g (13.67 mmol) of a 2-propanol solvate of a paroxetinehydrochloride anhydrate (containing about 3% by weight of 2-propanol)under nitrogen gas stream, and the mixture was heated to 52° C. Next, 40mL of water was added thereto at 48° to 49° C. In the course of coolingthe mixture to 5° C., crystals separated out at 43° C. After beingstirred at 43° to 45° C. for 30 minutes and kept at 2° to 5° C. underice cooling for 30 minutes, the mixture was filtered at the sametemperature. The residue was washed with 5 mL of water, to give wetcrystals (white). The crystals were dried under reduced pressure at 60°C., to give 4.80 g of crystals (white) of a paroxetine hydrochloride ½hydrate (yield: 93.7% by weight).

EXAMPLE 13

To a mixed solution of 7.05 g of 2-propanol, 7.41 g of water and 0.14 gof 35% hydrochloric acid (equivalent to 1.367 mmol of hydrogen chloride)was added 5.00 g (13.67 mmol) of a 2-propanol solvate of a paroxetinehydrochloride anhydrate (containing about 3% by weight of 2-propanol)under nitrogen gas stream, and the mixture was heated to 45° C. Next, 35mL of water was added thereto at 45° to 50° C. In the course of coolingthe mixture to 5° C., crystals separated out at 36° C. After beingstirred at 36° to 38° C. for 30 minutes and kept at 2° to 5° C. underice cooling for 30 minutes, the mixture was filtered at the sametemperature. The residue was washed with 5 mL of water, to give wetcrystals (white). The crystals were dried under reduced pressure at 60°C., to give 4.78 g of crystals (white) of a paroxetine hydrochloride ½hydrate (yield: 93.3% by weight).

EXAMPLE 14

To a solution of 37.5 g of water and 0.11 g of 35% hydrochloric acid wasadded 3.75 g (10.25 mmol) of a 2-propanol solvate of a paroxetinehydrochloride anhydrate under nitrogen gas stream, and the mixture washeated to 75° C. After the solvate was dissolved, the mixture wascooled. As a result, crystals separated out at 53° C., and the mixturewas solidified at 50° C. Subsequently, 18.8 g of water was addedthereto, to suspend the crystals. The suspension was then cooled andfiltrated at 24° C. The residue was washed with 3.75 g of water, to givewet crystals. The crystals were dried under reduced pressure at 60° C.,to give 3.34 g of crystals (white) of a paroxetine hydrochloride ½hydrate (yield: 87.0% by weight). The XRD agreed with that of areference material. The water content was 2.36% by weight (theoreticalwater content: 2.40% by weight). The pH of the supernatant of asuspension prepared by suspending 1 g of the crystals in 10 g ofdistilled water was 5.41.

On the other hand, the crystals obtained in the same manner as inrecrystallization in water in the absence of hydrochloric acid disclosedin JP-B-6-47587 and item (b) of Example 3 of European Patent No. 223403showed pink color under both of wet conditions and dry conditions. ThepH of the supernatant of a suspension prepared by suspending 1 g of thecrystals in 10 g of distilled water was 6.30.

EXAMPLE 15

To a mixed solution of 7.5 g of 2-propanol, 7.4 g of water and 0.14 g(equivalent to 1.367 mmol of hydrogen chloride) of 35% hydrochloric acidwas added 5.00 g (13.67 mmol) of a 2-propanol solvate of a paroxetinehydrochloride anhydrate (containing about 3% by weight of 2-proapnol)under nitrogen gas stream, and the mixture was heated under reflux (82°C.) for 1 hour, to dissolve the solvate. Next, when the temperatureattained to about 50° C., 25 mL of water was added thereto, and themixture was cooled to 5° C. After being kept at 2 to 5° C. for 1 hour,the mixture was filtered at the same temperature. The residue was washedwith 5 mL of water, to give wet crystals (white). The crystals weredried under reduced pressure at 60° C., to give crystals (white) of aparoxetine hydrochloride ½ hydrate. The pH of the supernatant of asuspension prepared by suspending 1 g of the crystals in 10 g ofdistilled water was 4.96.

On the other hand, the crystals of a paroxetine hydrochloride ½ hydratewere prepared in the same manner as mentioned above except that 35%hydrochloric acid was not added. The crystals showed pink color underboth of wet conditions and dry conditions. The pH of the supernatant ofa suspension prepared by suspending 1 g of the crystals in 10 g ofdistilled water was 6.99.

From these results, it can be seen that crystals of a paroxetinehydrochloride ½ hydrate efficiently separate out in a solvent forcrystallization according to Invention 1, and that white crystals of aparoxetine hydrochloride ½ hydrate which are not colored in pinkefficiently separate out according to Invention 2.

INDUSTRIAL APPLICABILITY

Crystals of a paroxetine chloride ½ hydrate can be utilized as anantidepressant.

1. A method for producing crystals of paroxetine hydrochloride ½-hydratecomprising adding water to a solution or suspension comprisingparoxetine hydrochloride and a polar organic solvent which contains atmost 60% by weight of water, to adjust the water content of saidsolution or suspension to at least 70% by weight whereby crystals ofparoxetine hydrochloride ½-hydrate are caused to separate out in saidwater-containing polar organic solvent.
 2. The method according to claim1, wherein a solution or suspension of a solid or oily paroxetinehydrochloride is initially prepared, and water is added to the solutionor suspension to adjust the water content to at least 70% by weight. 3.The method according to claim 1, wherein a solution or suspension ofcrystals of paroxetine hydrochloride is initially prepared, and water isadded to the solution or suspension to adjust the water content to atleast 70% by weight.
 4. The method according to claim 1, wherein asolution or suspension of crystals of paroxetine hydrochloride anhydrateis initially prepared, and water is added to the solution or suspensionto adjust the water content to at least 70% by weight.
 5. The methodaccording to claim 1, wherein a solution or suspension of crystals of2-propanol solvate of paroxetine hydrochloride anhydrate obtained bycrystallization from 2-propanol is initially prepared, and water isadded to the solution or suspension to adjust the water content to atleast 70% by weight.
 6. The method according to claim 1, wherein asolution or suspension of crystals of paroxetine hydrochloride ½-hydrateis initially prepared, and water is added to the solution or suspensionto adjust the water content to at least 70% by weight.
 7. The methodaccording to claim 1, wherein water is added to a solution or suspensioncomprising paroxetine hydrochloride and a polar organic solventcontaining 15 to 55% by weight of water.
 8. The method according toclaim 1, wherein water is added to a solution or suspension comprisingparoxetine hydrochloride and a polar organic solvent containing 20 to50% by weight of water.
 9. The method according to claim 1, whereinwater is added to the solution or suspension comprising paroxetinehydrochloride at a temperature of 40° to 60° C.
 10. The method accordingto claim 1, wherein water is added to the solution or suspension ofparoxetine hydrochloride, and then the resulting solution or suspensionis cooled to a temperature of 0° to 10° C.
 11. The method according toclaim 1, wherein the polar organic solvent is a lower alcohol having 1to 5 carbon atoms or a ketone.
 12. The method according to claim 11,wherein the lower alcohol is 2-propanol.
 13. The method according toclaim 1, wherein hydrogen chloride is present in the solution orsuspension of paroxetine hydrochloride.
 14. A method for producingcrystals of paroxetine hydrochloride ½-hydrate wherein crystals ofparoxetine hydrochloride ½-hydrate are allowed to separate out from asolution or suspension of paroxetine hydrochloride in which water or awater-containing polar organic solvent is used as a solvent in thepresence of hydrogen chloride, with the proviso that concentratedhydrochloric acid is not added to an aqueous solution of paroxetineacetate.
 15. The method according to claim 14, wherein the pH of thesolution or suspension of paroxetine hydrochloride is at most
 2. 16. Themethod according to claim 14, wherein a solution or suspension of asolid or oily paroxetine hydrochloride is initially prepared, and wateris added to the solution or suspension to adjust the water content to atleast 70% by weight.
 17. The method according to claim 14, wherein asolution or suspension of crystals of paroxetine hydrochloride isinitially prepared, and water is added to the solution or suspension toadjust the water content to at least 70% by weight.
 18. The methodaccording to claim 14, wherein a solution or suspension of crystals ofparoxetine hydrochloride anhydrate is initially prepared, and water isadded to the solution or suspension to adjust the water content to atleast 70% by weight.
 19. The method according to claim 18, wherein thecrystals of paroxetine hydrochloride anhydrate are crystals of2-propanol solvate of paroxetine hydrochloride anhydrate obtained bycrystallization in 2-propanol.
 20. The method according to claim 14,wherein a solution or suspension of crystals of paroxetine hydrochloride½-hydrate is initially prepared, and water is added to the solution orsuspension to adjust the water content to at least 70% by weight.
 21. Aprocess for preparing crystals of paroxetine hydrochloride ½-hydratebeing not colored in pink, comprising dissolving crystals of paroxetinehydrochloride ½-hydrate being colored in pink in a solvent, and allowingthe crystals to separate out wherein the crystals are recovered fromsaid solvent in the presence of hydrogen chloride in an amount at leastequimolar with the paroxetine hydrochloride ½-hydrate.